Smoking maintains its grip on over 40 million Americans, resulting in devastating illness, grievous economic loss, and tragic death for over 480,000 Americans each year. Tobacco use is the leading preventable cause of cancer, directly responsible for 1/3 of cancer deaths. This profound toll would be dramatically reduced if we substantially boosted rates of cessation among the 70% of smokers making healthcare visits each year. Despite multiple effective smoking treatments, and despite powerful health information technologies such as the electronic health record (EHR), far too few smokers get effective treatment during their healthcare visits. This is largely due to a failure of translatioal science; much translation of treatment research occurs by guesswork and hunch. This R35 Outstanding Investigator proposal will address the great need for translation of tobacco science via a unique set of real-world partners: a Wisconsin health system that will serve as a primary care laboratory, the world's leading EHR vendor, and a nationally renowned tobacco cessation research team led by the PI, Michael Fiore. These partners propose to: 1) develop and apply highly efficient and novel research methods to advance methodologically principled intervention translation, 2) design and test a highly efficient EHR-based treatment support system that organizes tobacco cessation treatment and fosters its dissemination, and 3) increase treatment effectiveness by delivering truly comprehensive chronic care smoking treatment to primary care patients. Thus, EHR changes and groundbreaking research methods will be used to re-engineer healthcare delivery systems to efficiently and seamlessly organize and deliver state-of-the-art treatment to the great majority of the nearly 30 million smokers visiting primary care settings each year. The smoking treatment and its support system will be designed for ready dissemination across health systems and diverse EHR platforms. The translational research methods should benefit any attempt to translate preventive health interventions. The proposed Principal Investigator has a 26-year track record of reducing tobacco use and its resulting harms. His experiences as a practicing physician, tobacco control scientist, and designer of national smoking policies, reflect enormous potential to fulfill the goals of the R35 mechanism - to revolutionize the delivery of tobacco use treatment so as to prevent literally millions of cance deaths.